Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis

Wen, Yaran; Liu, Yang; Xu, Yiming; Zhao, Yiwei; Hua, Rui; Wang, Kaibo; Sun, Miao; Li, Yuanhong; Yang, Sen; Zhang, Xue Jun; Kruse, Roland; Cichon, Sven; Betz, Regina C.; Nöthen, Markus M.; Steensel, M.A.M. van; Geel, Michel van; Steijlen, P.M.; Hohl, Daniel; Huber, Marcel; Dunnill, Giles; Kennedy, Cameron; Messenger, A.G.; Munro, Colin S.; Terrinoni, Alessandro; Hovnanian, Alain; Bodemer, Christine; Prost, Y. De; Paller, Amy S.; Irvine, Alan D.; Sinclair, Rodney; Green, Jack; Shang, Donghao; Liu, Qing; Luo, Yang; Jiang, Li; Chen, Hong Duo; Lo, Wilson H.Y.; McLean, W.H. Irwin; He, Chun Di; Zhang, Xue

doi:10.1038/ng.276

Cited by 186 publications

(194 citation statements)

References 28 publications

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“…Second, a mutation introducing a uORF into CDKN2A causes a familial predisposition to melanoma (4). Third, disruption of uORF presence and coding sequence in gene HR causes Marie Unna hereditary hypotrichosis (5). Additional uORF-altering mutations detected in patients with 11 diseases have been reported in the literature, although they were not followed up experimentally (Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…uORFs have been shown to reduce protein levels in Ϸ100 eukaryotic genes [supporting information (SI) Table S1]. Additionally, mutations that introduce or disrupt a uORF have found to cause 3 human diseases (3)(4)(5). In several interesting cases, the uORF-derived protein is functional; however, in most cases, the mere presence of the uORF is sufficient to reduce expression of the downstream ORF (1,2,(6)(7)(8).…”

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confidence: 99%

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Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

Calvo

Pagliarini

Mootha

2009

Proc. Natl. Acad. Sci. U.S.A.

798

899

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Upstream ORFs (uORFs) are mRNA elements defined by a start codon in the 5 UTR that is out-of-frame with the main coding sequence. Although uORFs are present in approximately half of human and mouse transcripts, no study has investigated their global impact on protein expression. Here, we report that uORFs correlate with significantly reduced protein expression of the downstream ORF, based on analysis of 11,649 matched mRNA and protein measurements from 4 published mammalian studies. Using reporter constructs to test 25 selected uORFs, we estimate that uORFs typically reduce protein expression by 30 -80%, with a modest impact on mRNA levels. We additionally identify polymorphisms that alter uORF presence in 509 human genes. Finally, we report that 5 uORF-altering mutations, detected within genes previously linked to human diseases, dramatically silence expression of the downstream protein. Together, our results suggest that uORFs influence the protein expression of thousands of mammalian genes and that variation in these elements can influence human phenotype and disease.polymorphism ͉ post-transcriptional control ͉ proteomics ͉ translation ͉ uORF

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

Calvo

Pagliarini

Mootha

2009

Proc. Natl. Acad. Sci. U.S.A.

798

899

View full text Add to dashboard Cite

show abstract

“…In humans, approximately half of annotated transcripts contain uORFs, and presence of uORFs is widely polymorphic across individuals (Supplemental Table S5; Calvo et al 2009;Barbosa et al 2013;Waern and Snyder 2013). Disruption of a uORF in the HR gene has been previously shown to lead to Marie Unna hereditary hypotrichosis by modulating the translation of the main ORF, suggesting that human disease can be associated with changes in uORFs (Wen et al 2009). …”

Section: The Role Of Uorfs In Modulating Ribosome Occupancymentioning

confidence: 99%

“…Specifically, we utilized SAMtools mpileup utility in combination with BCFtools (Li et al 2009) Genotype data and processing We included all variant calls provided by both release and pilot data sets without additional score or source filtering. We subsetted all single nucleotide polymorphisms (SNPs) that overlap APPRIS transcripts and retained all phasing information from the VCF files.…”

Section: Ribosome Profiling Sample Identity Verificationmentioning

confidence: 99%

Integrative analysis of RNA, translation, and protein levels reveals distinct regulatory variation across humans

et al. 2015

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Elucidating the consequences of genetic differences between humans is essential for understanding phenotypic diversity and personalized medicine. Although variation in RNA levels, transcription factor binding, and chromatin have been explored, little is known about global variation in translation and its genetic determinants. We used ribosome profiling, RNA sequencing, and mass spectrometry to perform an integrated analysis in lymphoblastoid cell lines from a diverse group of individuals. We find significant differences in RNA, translation, and protein levels suggesting diverse mechanisms of personalized gene expression control. Combined analysis of RNA expression and ribosome occupancy improves the identification of individual protein level differences. Finally, we identify genetic differences that specifically modulate ribosome occupancy-many of these differences lie close to start codons and upstream ORFs. Our results reveal a new level of gene expression variation among humans and indicate that genetic variants can cause changes in protein levels through effects on translation.

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“…In the same vein, upstream open reading frames (uORFs), present in $50% of human genes, often impact upon the expression of the primary ORFs; indeed, both mutations and polymorphisms have been reported within uORFs that can modulate or even abolish the expression of the downstream gene [Calvo et al, 2009;Wen et al, 2009].…”

Section: Mutations Residing Within Proximal Gene Regulatory Regionsmentioning

confidence: 99%

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

et al. 2010

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The number of reported germline mutations in human nuclear genes, either underlying or associated with inherited disease, has now exceeded 100,000 in more than 3,700 different genes. The availability of these data has both revolutionized the study of the morbid anatomy of the human genome and facilitated “personalized genomics.” With ∼300 new “inherited disease genes” (and ∼10,000 new mutations) being identified annually, it is pertinent to ask how many “inherited disease genes” there are in the human genome, how many mutations reside within them, and where such lesions are likely to be located? To address these questions, it is necessary not only to reconsider how we define human genes but also to explore notions of gene “essentiality” and “dispensability.” Answers to these questions are now emerging from recent novel insights into genome structure and function and through complete genome sequence information derived from multiple individual human genomes. However, a change in focus toward screening functional genomic elements as opposed to genes sensu stricto will be required if we are to capitalize fully on recent technical and conceptual advances and identify new types of disease‐associated mutation within noncoding regions remote from the genes whose function they disrupt. Hum Mutat 31:631–655, 2010. © 2010 Wiley‐Liss, Inc.

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Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis

Cited by 186 publications

References 28 publications

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

Integrative analysis of RNA, translation, and protein levels reveals distinct regulatory variation across humans

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

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